Role of PITRM1 in Mitochondrial Dysfunction and Neurodegeneration

Mounting evidence shows a link between mitochondrial dysfunction and neurodegenerative disorders, including Alzheimer Disease. Increased oxidative stress, defective mitodynamics, and impaired oxidative phosphorylation leading to decreased ATP production, can determine synaptic dysfunction, apoptosis, and neurodegeneration. Furthermore, mitochondrial proteostasis and the protease-mediated quality control system, carrying out degradation of potentially toxic peptides and misfolded or damaged proteins inside mitochondria, are emerging as potential pathogenetic mechanisms. The enzyme pitrilysin metallopeptidase 1 (PITRM1) is a key player in these processes; it is responsible for degrading mitochondrial targeting sequences that are cleaved off from the imported precursor proteins and for digesting a mitochondrial fraction of amyloid beta (Aβ). In this review, we present current evidence obtained from patients with PITRM1 mutations, as well as the different cellular and animal models of PITRM1 deficiency, which points toward PITRM1 as a possible driving factor of several neurodegenerative conditions. Finally, we point out the prospect of new diagnostic and therapeutic approaches.

Behavior and body size modulate the defense of toxin-containing sawfly larvae against ants

The sawfly larvae of most Argidae and Pergidae (Hymenoptera: Symphyta) species contain toxic peptides, and these along with other traits contribute to their defense. However, the effectiveness of their defense strategy, especially against ants, remains poorly quantified. Here, five Arge species, A. berberidis, A. nigripes, A. ochropus, A. pagana, A. pullata, plus three Pergidae species, Lophyrotoma analis, Lophyrotoma zonalis, Philomastix macleaii, were tested in laboratory bioassays on ant workers mainly of Myrmica rubra. The experiments focused on short-term predator–prey interactions, sawfly survival rate after long-term interactions, and feeding deterrence of the sawfly hemolymph. The larvae of Arge species were generally surrounded by few ants, which rarely bit them, whereas larvae of Pergidae, especially P. macleaii, had more ants around with more biting. A detailed behavioral analysis of Arge-ant interactions revealed that larval body size and abdomen raising behavior were two determinants of ant responses. Another determinant may be the emission of a volatile secretion by non-eversible ventro-abdominal glands. The crude hemolymph of all tested species, the five Arge species and L. zonalis, was a strong feeding deterrent and remained active at a ten-fold dilution. Furthermore, the study revealed that the taxon-specific behavior of ants, sting or spray, impacted the survival of A. pagana but not the large body-sized A. pullata. The overall results suggest that the ability of Arge and Pergidae larvae to defend against ants is influenced by the body size and behavior of the larvae, as well as by chemicals.

Prediction of Anticancer Peptides with High Efficacy and Low Toxicity by Hybrid Model Based on 3D Structure of Peptides

Recently, anticancer peptides (ACPs) have emerged as unique and promising therapeutic agents for cancer treatment compared with antibody and small molecule drugs. In addition to experimental methods of ACPs discovery, it is also necessary to develop accurate machine learning models for ACP prediction. In this study, features were extracted from the three-dimensional (3D) structure of peptides to develop the model, compared to most of the previous computational models, which are based on sequence information. In order to develop ACPs with more potency, more selectivity and less toxicity, the model for predicting ACPs, hemolytic peptides and toxic peptides were established by peptides 3D structure separately. Multiple datasets were collected according to whether the peptide sequence was chemically modified. After feature extraction and screening, diverse algorithms were used to build the model. Twelve models with excellent performance (Acc > 90%) in the ACPs mixed datasets were used to form a hybrid model to predict the candidate ACPs, and then the optimal model of hemolytic peptides (Acc = 73.68%) and toxic peptides (Acc = 85.5%) was used for safety prediction. Novel ACPs were found by using those models, and five peptides were randomly selected to determine their anticancer activity and toxic side effects in vitro experiments.

Impacts of the Type I Toxin–Antitoxin System, SprG1/SprF1, on Staphylococcus aureus Gene Expression

Type I toxin–antitoxin (TA) systems are widespread genetic modules in bacterial genomes. They express toxic peptides whose overexpression leads to growth arrest or cell death, whereas antitoxins regulate the expression of toxins, acting as labile antisense RNAs. The Staphylococcus aureus (S. aureus) genome contains and expresses several functional type I TA systems, but their biological functions remain unclear. Here, we addressed and challenged experimentally, by proteomics, if the type I TA system, the SprG1/SprF1 pair, influences the overall gene expression in S. aureus. Deleted and complemented S. aureus strains were analyzed for their proteomes, both intracellular and extracellular, during growth. Comparison of intracellular proteomes among the strains points to the SprF1 antitoxin as moderately downregulating protein expression. In the strain naturally expressing the SprG1 toxin, cytoplasmic proteins are excreted into the medium, but this is not due to unspecific cell leakages. Such a toxin-driven release of the cytoplasmic proteins may modulate the host inflammatory response that, in turn, could amplify the S. aureus infection spread.

Defects in translation-dependent quality control pathways lead to convergent molecular and neurodevelopmental pathology

Translation-dependent quality control pathways such as no-go decay (NGD), non-stop decay (NSD), and nonsense-mediated decay (NMD) govern protein synthesis and proteostasis by resolving non-translating ribosomes and preventing the production of potentially toxic peptides derived from faulty and aberrant mRNAs. However, how translation is altered and the in vivo defects that arise in the absence of these pathways are poorly understood. Here, we show that the NGD/NSD factors Pelo and Hbs1l are critical in mice for cerebellar neurogenesis but expendable for survival of these neurons after development. Analysis of mutant mouse embryonic fibroblasts revealed translational pauses, alteration of signaling pathways, and translational reprogramming. Similar effects on signaling pathways, including mTOR activation, the translatome and mouse cerebellar development were observed upon deletion of the NMD factor Upf2. Our data reveal that these quality control pathways that function to mitigate errors at distinct steps in translation can evoke similar cellular responses.

Efficient Hydrolysis of Gluten-Derived Celiac Disease-Triggering Immunogenic Peptides by a Bacterial Serine Protease from Burkholderia gladioli

Celiac disease is an autoimmune disorder triggered by toxic peptides derived from incompletely digested glutens in the stomach. Peptidases that can digest the toxic peptides may formulate an oral enzyme therapy to improve the patients’ health condition. Bga1903 is a serine endopeptidase secreted by Burkholderia gladioli. The preproprotein of Bga1903 consists of an N-terminal signal peptide, a propeptide region, and an enzymatic domain that belongs to the S8 subfamily. Bga1903 could be secreted into the culture medium when it was expressed in E. coli. The purified Bga1903 is capable of hydrolyzing the gluten-derived toxic peptides, such as the 33- and 26-mer peptides, with the preference for the peptide bonds at the carbonyl site of glutamine (P1 position). The kinetic assay of Bga1903 toward the chromogenic substrate Z-HPQ-pNA at 37 °C, pH 7.0, suggests that the values of Km and kcat are 0.44 ± 0.1 mM and 17.8 ± 0.4 s−1, respectively. The addition of Bga1903 in the wort during the fermentation step of beer could help in making gluten-free beer. In summary, Bga1903 is usable to reduce the gluten content in processed foods and represents a good candidate for protein engineering/modification aimed to efficiently digest the gluten at the gastric condition.

Defects in translation-dependent quality control pathways lead to convergent molecular and neurodevelopmental pathology

Translation-dependent quality control pathways such as no-go decay (NGD), non-stop decay (NSD) and nonsense-mediated decay (NMD) govern protein synthesis and proteostasis by resolving non-translating ribosomes and preventing the production of potentially toxic peptides derived from faulty and aberrant mRNAs. However, how translation is altered and the in vivo defects that arise in the absence of these pathways are poorly understood. Here, we show that the NGD/NSD factors Pelo and Hbs1l are critical for cerebellar neurogenesis but expendable for survival of these neurons after development. Analysis of mutant embryonic fibroblasts revealed translational pauses, alteration of signaling pathways, and translational reprogramming. Similar effects on signaling pathways, the translatome and cerebellar development were observed upon deletion of the NMD factor Upf2. These data reveal that these quality control pathways that function to mitigate errors at distinct steps in translation can evoke similar cellular responses.

Epidemiological dynamics of bacteriocin competition and antibiotic resistance

Bacteriocins, toxic peptides involved in bacterial fratricide, are extremely diverse. Understanding the mechanisms that maintain this diversity is an important aim in bacterial ecology. Previous work on bacteriocin diversity has focused on dynamics, particularly ‘rock-paper-scissors’ dynamics, at the within-host scale. Yet, in species such as Streptococcus pneumoniae, with relatively short periods of colonisation and limited within-host diversity, processes at the epidemiological scale also shape eco-evolutionary dynamics. Here, we investigate bacteriocin dynamics in epidemiological models. We find that in these models, bacteriocin diversity arises more readily than in within-host models, and with more possible combinations of coexisting bacteriocin profiles. We also investigate a potential link between bacteriocin diversity and diversity at antibiotic resistance loci. Previous work has proposed that bacterial duration of carriage modulates the fitness of antibiotic resistance. We predict bacteriocins modulate duration of carriage, making them a plausible candidate for involvement in resistance dynamics.

The Human Digestive Tract Is Capable of Degrading Gluten from Birth

The human gastrointestinal system has the capacity to metabolize dietary gluten. The capacity to degrade gliadin-derived peptide is present in humans from birth and increases during the first stages of life (up to 6–12 months of age). Fecal samples from 151 new-born and adult non-celiac disease (NCD) volunteers were collected, and glutenase and glianidase activities were evaluated. The capacity of total fecal proteins to metabolize 33-mer, 19-mer, and 13-mer gliadin peptides was also evaluated by high-performance liquid chromatography (HPLC). Feces from new-borns (meconium) showed glutenase and gliadinase activities, and peptidase activity against all three gliadin peptides. Maximal gluten degradative activity was observed in fecal samples from the youngest volunteers (0–12 months old). After the age of nine months, the gluten digestive capacity of gastrointestinal tract decreases and, from ±8 years old, individuals lose the ability to completely degrade toxic peptides. The gastrointestinal proteases involved in gluten digestion: elastase 2A, elastase 3B, and carboxipeptidase A1 are present from earlier stages of life. The human digestive tract contains the proteins capable of metabolizing gluten from birth, even before starting gluten intake. Humans are born with the ability to digest gluten and to completely degrade the potentially toxic gliadin-derived peptides (33-, 19-, and 13-mer).

Reducing Immunoreactivity of Gliadins and Coeliac-Toxic Peptides Using Peptidases from L. acidophilus 5e2 and A. niger

Wheat storage proteins and products of their hydrolysis may cause coeliac sprue in genetically predisposed individuals with high expression of main histocompatibility complex HLA-DQ2 or DQ8, since by consuming wheat, they become exposed to proline- (P) and glutamine (Q)-rich gluten. In bread-making, the hydrolysis of gliadins and coeliac-toxic peptides occurs with varied efficiency depending on the fermentation pH and temperature. Degradation of gliadins catalysed by Lactobacillus acidophilus 5e2 peptidases and a commercial prolyl endopeptidase synthesised by A. niger, carried out at pH 4.0 and 37 °C, reduces the gliadin concentration over 110-fold and decreases the relative immunoreactivity of the hydrolysate to 0.9% of its initial value. Hydrolysis of coeliac-toxic peptides: LGQQQPFPPQQPY (P1) and PQPQLPYPQPQLP (P2) under the same conditions occurs with the highest efficiency, reaching 99.8 ± 0.0% and 97.5 ± 0.1%, respectively. The relative immunoreactivity of peptides P1 and P2 was 0.8 ± 0.0% and 3.2 ± 0.0%, respectively. A mixture of peptidases from L. acidophilus 5e2 and A. niger may be used in wheat sourdough fermentation to reduce the time needed for degradation of proteins and products of their hydrolysis.